The goal of this integrated Program Project application is to get fusion of HIV-1 with target cells as a means to protect against transmucosal transmission of infection. The studies will focus initially on amino-terminus modified RANTES analogues as designed and tested by team members that target the CCR5 HIV-1 co-receptor and then on the combinations of RANTES analogues and other fusion inhibitors such as C-34 and 5-Helix that target the HIV-l gp41 molecule. Project 1 will provide a full pharmacologic activity profile for the lead molecule - PSC-RANTES and will screen a large library of RANTES analogues to identify structures with greater receptor specificities and optimal viral inhibition/agonist activity. Project 2 will test the in vitro activity of RANTES analogues in combination with 5-Helix, C-34 and derived compounds for synergistic inhibition of HIV-1 infection of primary T cells and epidermal Langerhans cells. Additional studies will examine the replicative fitness of viral isolates that emerge resistant to these compounds (from Project 3). Project 3 will test the activities of these agents in the hu-PBL-SCID model, will determine if suboptimal concentrations of compounds select for emergence of resistant isolates and will develop this model for recruitment of human T cells to skin grafts as a model for transepithelial HIV-1 transmission. Project 4 will provide preclinical safety and activity testing of PSC-RANTES (and other compounds warranted) after intravaginal application in macaques to support early human safety trials. Project 5 will examine the CCR5 promoter and open reading frame polymorphisms in Ugandans and will examine the effect of these polymorphisms on CCR5 expression, HIV-1 replication and activities of PSCRANTES. Project 6 proposes to conduct small Phase I studies in the US and in Uganda to evaluate the safety of PSC-RANTES. Additional studies will monitor the systemic absorption, intravaginal elimination half-life and effects on cellular composition, cytokine, chemokine, and CR5 expression after intravaginal application of PSC-RANTES and related compounds.